The focus of our efforts is to use a molecular understanding of immune function to develop safe and consistently effective immune based treatments for patients whose cancers are not currently treatable with traditional approaches such as chemotherapy, radiation and surgery. Our approach is to create mouse models to enable us to understand the basic immunology of the tumor-host interaction and to develop and pre-clinically test new treatments for patients. Data obtained from clinical trials based on experimental approaches are then used to generate new hypotheses, which are explored in the laboratory. We have now identified and cloned the mouse homologs of human tumor associated antigens and used these in the creation of recombinant and synthetic anticancer vaccines, including recombinant viruses, "naked" DNA immunogens, proteins and peptides. We have optimized the functions of a variety of vaccines and learned how stimulate anti-tumor immune responses in animal models and in patients with cancer. One consequence of successful tumor immunotherapy with the T cell growth factor, interleukin-2 can be vitiligo, the patchy and usually permanent loss of pigment from the skin. We have successfully developed a mouse model for vitiligo, in which we can prevent the growth of an experimental mouse melanoma. Despite considerable advances in our understanding of the molecular basis of immune-tumor interactions, we are not yet able to consistently destroy tumor cells in patients with melanoma. We have learned that merely increasing T cell precursor frequency can be insufficient to induce anti-tumor immune responses. In order to understand how to improve therapeutic effectiveness of experimental anti-tumor vaccines we have employed mice that are transgenic for human MHC molecules (such as HLA-A2 and HLA-DR4). We also use mice that are knocked out for the antigens that we are targeting, enabling us to assess the roles for immunological tolerance to these antigens. Most recently, we have created mice that are transgenic for T cell receptors, and these mice make it possible for us to study tumor-specific T cells in a variety of activation states. In the immediate future, we plan to focus our research efforts on extending efforts to develop effective therapeutic cancer vaccines, including alphavirus replicase-based vectors for research and clinical use. Experimental vaccines will be used to explore issues surrounding the function (and non-function) of T cells that are elicited by experimental vaccines including the tolerance and apoptosis of anti-tumor T cells. An increased understanding at the molecular level of T cell activation, function and death has led us to genetically manipulate T cell function using transgenic mice. Ongoing research efforts include the conferring of new specificities to T cells (eg. insertion of new T cell receptors), enhancing the expression of pro-survival genes (eg. bcl-2) in anti-tumor T cells, knocking out negative regulators of T cell function (eg. CTLA-4), and genetically interfering with apoptotic pathways (eg. Fas-FasL).